In 2000, a group of scientists at Columbia University were awarded a large P42 Superfund Research Program grant from NIEHS entitled Health Effects and Geochemistry of Arsenic and Manganese. That grant, now competitively renewed twice, has focused on the global public health problems that arise as a consequence of the consumption of well water that is naturally enriched in arsenic (As) and/or manganese (Mn). The World Health Organization (WHO) estimates that more than 140 million people are chronically exposed to elevated concentrations of As alone. While our work includes projects in the U.S. (Maine, New Hampshire and New Jersey), the primary focus of our work has been a set of projects that take place in Bangladesh, where roughly 40 million people have been chronically exposed to both toxic elements since the early 1970s, when UNICEF installed roughly one million wells to reduce the burden of diarrheal disease from drinking surface water. Over the past decade, our P42 grant has spun off nine R01 grants to the four investigators in the current proposal; the four investigators were once all at Columbia University but are now spread across three institutions, i.e., Columbia, NYU and the University of Chicago. Our research has relied on a Perkin-Elmer Inductively Coupled Plasma Mass Spectrometer (ICP-MS) which is now 12 years old and in need of replacement. The ICP-MS is used to simultaneously measure the concentrations of As, Mn, Pb and Se in blood, and to measure the proportions of six metabolites of As in blood and urine. Over the past seven years alone, nearly 18,000 biological samples have been analyzed by this instrument. The work of Dr. Joseph Graziano has focused on the consequences of exposure to As and excess Mn on children. Dr. Mary Gamble has conducted landmark studies that indicate that the folate status of Bangladeshi study participants profoundly influences As metabolism and toxicity, and that folic acid supplementation facilitates As methylation (i.e., detoxification) and elimination, thereby lowering blood As. Dr. Habibul Ahsan has served as the PI of a longitudinal prospective cohort study entitled Health Effects of Arsenic Longitudinal Study (HEALS). This project recruited 12,000 adults in Bangladesh in 2000, and increased its sample size to 24,000 participants in 2006. The HEALS study has produced a series of landmark findings concerning dose- response relationships between exposure and neuropathy, pulmonary disease, skin lesions, and chronic disease mortality, as well as a host of factors that act as effect modifiers. Finally, Dr.Yu Chen's research has focused on the remarkable cardiovascular effects of As.